DUX4 at 25: how it emerged from "junk DNA" to become the cause of facioscapulohumeral muscular dystrophy.

Double Homeobox 4 (DUX4) is a potent transcription factor encoded by a retrogene mapped in D4Z4 repeated elements on chromosome 4q35. DUX4 has emerged as pivotal in the pathomechanisms of facioscapulohumeral muscular dystrophy (FSHD), a relatively common hereditary muscle wasting condition, although classified as a rare disease. DUX4 contributes to zygote genome activation before its expression is repressed in most somatic tissues through epigenetic mechanisms, including DNA methylation and chromatin modifications. In FSHD, inappropriate activation of DUX4 expression is driven by a complex interplay of genomic and epigenetic alterations. The ectopic presence of DUX4 in skeletal muscle cells activates genes, viral elements and pathways that are typical of very early embryonic development, disturbing cell function and ultimately contributing to muscle weakness and wasting. This review first traces the history of DUX4, from the FSHD genetic linkage studies in the early 1990s, through to identification and characterization of the DUX4 gene in 1999. We then discuss the seminal studies that showed how and why DUX4 is expressed in FSHD and the effects of this ectopic expression in muscle, notably cellular toxicity. Other pathological roles of DUX4, such as participation in cancer and viral infection, are also highlighted. Maintenance of DUX4 in the genome was explained by discovery of the function of DUX4 in zygotic genome activation to institute the totipotent cells of the embryo. Thus, we encompass the gradual transition of DUX4 over the past 25 years from being considered a pseudogene in "junk DNA" to becoming central to understanding the molecular pathogenesis of FSHD and the primary focus for FSHD therapeutics.